WO2017066538A1 - Combinaison de sérotonine et d'une cytokine comme prédicteur pronostique précoce de la dengue grave - Google Patents

Combinaison de sérotonine et d'une cytokine comme prédicteur pronostique précoce de la dengue grave Download PDF

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WO2017066538A1
WO2017066538A1 PCT/US2016/056999 US2016056999W WO2017066538A1 WO 2017066538 A1 WO2017066538 A1 WO 2017066538A1 US 2016056999 W US2016056999 W US 2016056999W WO 2017066538 A1 WO2017066538 A1 WO 2017066538A1
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subject
concentration
vegf
gamma
ifn
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PCT/US2016/056999
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Liang CUI
Yie Hou LEE
Steven R. Tannenbaum
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Massachusetts Institute Of Technology
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56983—Viruses
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/005—Assays involving biological materials from specific organisms or of a specific nature from viruses
    • G01N2333/08—RNA viruses
    • G01N2333/18—Togaviridae; Flaviviridae
    • G01N2333/183—Flaviviridae, e.g. pestivirus, mucosal disease virus, bovine viral diarrhoea virus, classical swine fever virus (hog cholera virus) or border disease virus
    • G01N2333/185—Flaviviruses or Group B arboviruses, e.g. yellow fever virus, japanese encephalitis, tick-borne encephalitis, dengue
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease

Definitions

  • a rapid, quantitative assay for the combination of serotonin and a cytokine for the purpose of early prognosis of patients with propensity to develop severe dengue.
  • Quantitative information of serotonin and cytokine, e.g., interferon- gamma, concentrations can be used to determine specific concentration cutoffs to derive the best sensitivity (true positive) and specificity (true negative) to predict patients likely to develop severe dengue within the first 96 hours upon onset of fever.
  • the biological sample is a serum or urine sample. In some embodiments, the biological sample is obtained from the subject within 96 hours of onset of fever (>38.0°C). In some embodiments, the method further comprises managing treatment of the subject based on the statistically significant difference. In some embodiments, the managing treatment of a subject comprises hospitalization of the subject based on the presence of the statistically significant difference. In another aspect, the invention provides a kit or device for evaluating Dengue Fever infection. In some embodiments, the kit or device comprises one or more binding partners for serotonin and/or interferon-gamma, wherein the one or more binding partners are attached to a surface. In some embodiments, the device generates an output that indicates that a subject has or is at risk for DHF. In some embodiments, the kit or device further comprises at least one control binding agent. In some embodiments, the device is a dipstick.
  • FIG. 1 depicts the positive correlation between serotonin and platelet numbers.
  • FIG. 2 depicts the scatter plot of serotonin in serum samples of DF/DHF patients at different stages of the infection.
  • FIG. 3 depicts the prognostic performance of combining serotonin and interferon- gamma with receiver operator characteristics (ROC) analysis.
  • FIGs. 4A-4C depict the prognostic performance of (FIG. 4A) platelets alone, (FIG. 4B) serotonin only and (FIG. 4C) interferon-gamma only with receiver operator characteristic (ROC).
  • FIGs. 5A-5B summarize the concentration cutoffs of (FIG. 5A) interferon-gamma and (FIG. 5B) serotonin and their corresponding sensitivity and specificity in predicting severe dengue.
  • aspects of the invention relate to methods and devices for evaluating Dengue Virus infection, early prediction of DHF and DHF progression.
  • Previous studies have attempted to develop methods for early prediction of DHF by statistical analysis of a variety of clinical laboratory indicators.
  • Potts et al. reported a classification and regression tree (CART) analysis of clinical indicators from patient cohort of 1384 dengue-infected children in Thailand (Potts JA, Gibbons RV, Rothman AL, Srikiatkhachorn A, Thomas SJ, et al. (2010) Prediction of dengue disease severity among pediatric Thai patients using early clinical laboratory indicators.
  • CART classification and regression tree
  • PLoS Negl Trop Dis 4 e769; Potts JA, Thomas SJ, Srikiatkhachorn A, Supradish PO, Li W, et al. (2010) Classification of dengue illness based on readily available laboratory data.
  • Am J Trop Med Hyg 83 : 781-788 while Tanner et al employed a decision tree algorithm in a 1200 patient cohort from Singapore and Vietnam (Tanner L, Schreiber M, Low JG, Ong A, Tolfvenstam T, et al. (2008) Decision tree algorithms predict the diagnosis and outcome of dengue fever in the early phase of illness.
  • PLoS Negl Trop Dis 2 el96).
  • interferon-gamma IFN- ⁇
  • FGF basic basic fibroblast growth factor
  • G-CSF granulocyte-colony stimulating factor
  • IL-8 interleukin-8
  • interferon-gamma can be used as a first screen to capture as many patients likely to develop severe dengue (a test with high sensitivity /low specificity) and serotonin as a second screen to eliminate false positives (test with low sensitivity /high specificity) thereby keeping hospitalizations low.
  • serotonin can be used as a first screen to capture as many patients likely to develop severe dengue (a test with high sensitivity /low specificity) and serotonin as a second screen to eliminate false positives (test with low sensitivity /high specificity) thereby keeping hospitalizations low.
  • serotonin with interferon-gamma not only reflects the biology of dengue, but also provides quantitative, accurate metrics for the early ( ⁇ 96 h from onset of fever) prognosis of DHF.
  • Dengue Virus causes a collection of human illnesses ranging from mild Dengue Fever (DF) to potentially lethal Dengue Hemorrhagic Fever (DFIF) and Dengue Shock Syndrome (DSS). Viral transmission to humans occurs via the mosquito species of Aedes aegypti and Aedes albopictus. Dengue is endemic to tropical and sub-tropical regions of the world and with over 50-100 million annual cases of dengue infection. Dengue virus occurs in four distinct serotypes (DENV1-4) all of which can cause severe illnesses. A patient presenting symptoms such as fever, headache, muscle and joint pain, nausea and rashes may be exhibiting signs of DF.
  • the WHO has released guidelines for classification of dengue illnesses (Potts JA, Thomas SJ, Srikiatkhachorn A, Supradish PO, Li W, et al. (2010) Classification of dengue illness based on readily available laboratory data.
  • Am J Trop Med Hyg 83 : 781-788 which are often seen as a spectrum of conditions varying in severity from mild DF to life-threatening DHF and DSS.
  • DF patients who display thrombocytopenia ( ⁇ 100,000/dl) bleeding and plasma leakage are generally classified as DHF (Potts JA, Gibbons RV, Rothman AL, Srikiatkhachorn A, Thomas SJ, et al. (2010) Prediction of dengue disease severity among pediatric Thai patients using early clinical laboratory indicators.
  • PLoS Negl Trop Dis 4: e769) these symptoms become evident only in the critical phase of infection and currently it is not possible to distinguish DF and DHF during the early febrile stages.
  • methods described herein are useful to determine whether a subject having symptoms of a Dengue virus infection is likely to develop severe DHF as opposed to having a self-limiting disease.
  • the levels of serotonin and interferon- gamma described herein are indicative that a subject is more likely than not to develop severe DHF, then the subject is subsequently or immediately hospitalized.
  • a subject that is not hospitalized is monitored regularly (e.g., weekly, every 2-3 days, daily, more than once a day) to determine whether there are any indication that the infection is changing to a severe DHF.
  • the levels of serotonin and interferon-gamma described herein may be evaluated several times (e.g., weekly, every 2-3 days, daily, more than once a day) while a patient has other symptoms (e.g., a fever) associated with a Dengue virus infection.
  • serotonin and interferon-gamma described herein can be used to classify DHF and DF in subjects within about 96 hours of fever onset. This classification can be used to triage patients, e.g., by sending subjects suspected of having DHF to the hospital.
  • the Prospective Adult Dengue Study is a cohort study of acutely febrile adults at a tertiary care center, Communicable Diseases Center, Tan Tock Seng Hospital.
  • Adult patients > 18 years
  • presenting with acute onset of fever > 37.5°C
  • rhinitis or other clinical alternatives were included in the study (Febrile stage, ⁇ 96 hours post onset of fever; Defervescence, Day 5-7, Convalescence, Day 21-28).
  • Venous blood samples were collected, aliquoted and frozen at -80°C for hematological, virological and serological analysis.
  • the invention provides novel biomarkers useful for evaluating (e.g., identifying, assisting in identifying, diagnosing, assisting in diagnosing, triaging, or assisting in triaging) a subject with a disease caused by Dengue Virus, e.g., Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome.
  • the invention provides kits and devices useful for evaluating (e.g., identifying, assisting in identifying, diagnosing, assisting in diagnosing, triaging, or assisting in triaging) a subject with a disease caused by Dengue Virus, e.g., Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome.
  • the invention provides biomarkers, kits, and devices for use in evaluation of drug efficacy during clinical trials of potential drugs and vaccines for Dengue Virus.
  • the invention provides biomarkers, kits, and devices for use in epidemiological surveys of disease pathology of Dengue Virus.
  • the invention provides methods for early identification or determination of subjects at risk for developing or having developed DHF. In some embodiments, early identification occurs at the early febrile phase (e.g., less than about 96 hours after onset of fever (>38.0°C)).
  • the invention provides biomarkers for use in methods of evaluating (e.g., identifying, assisting in identifying, diagnosing, assisting in diagnosing, triaging, or assisting in triaging) a subject with a disease caused by Dengue Virus, e.g., Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome.
  • a disease caused by Dengue Virus e.g., Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome.
  • the methods described herein can be used in combination with other risk factors in evaluating a subject.
  • a biomarker is any organic molecule, e.g., metabolite, protein, DNA, RNA, adducts or any derivative thereof, or a biological entity, e.g., a cell or a virus, that can be used as an indicator of a disease state, e.g., Dengue Fever, Dengue Hemorrhagic Fever, or Dengue Shock Syndrome.
  • the biomarkers in this invention are serotonin (serum/urine metabolite) and cytokine (e.g., interferon-gamma) .
  • the combination of serotonin and cytokine e.g., interferon- gamma
  • cytokine e.g., interferon- gamma
  • the combination of serotonin and cytokine is used for evaluating a disease in a subject caused by Dengue Virus, e.g., Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome.
  • Dengue Virus e.g., Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome.
  • the method further comprises comparing the serotonin concentration in the sample with a control serotonin concentration. In some embodiments, the method further comprises comparing the one or more cytokine concentration selected from interferon-gamma, basic fibroblast growth factor, granulocyte-colony stimulating factor, interleukin-8, IL10, BDNF, VEGF-A, VEGF-D, IFN- alpha, TNF alpha, bNGF, HGF or PDGF-BB with one or more corresponding control cytokine concentration.
  • cytokine concentration selected from interferon-gamma, basic fibroblast growth factor, granulocyte-colony stimulating factor, interleukin-8, IL10, BDNF, VEGF-A, VEGF-D, IFN- alpha, TNF alpha, bNGF, HGF or PDGF-BB with one or more corresponding control cytokine concentration.
  • the levels of serotonin and cytokine are measured from a biological sample collected at one time point.
  • the time point is less than about 96 hours after onset of a fever in the subject (>38.0°C).
  • the expression levels of serotonin and cytokine, e.g., interferon-gamma are measured from a biological sample collected at more than one time points (e.g., at less than about 96 hours after fever onset, at about 5-7 days after fever onset, and at about 3-4 weeks after fever onset).
  • the biomarkers provided herein can be detected using any of a variety of detection agents (also referred to herein as "binding partners") known in the art, including antibody or antigen-binding fragment thereof, such as Fab, F(ab)2, Fv, single chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, scFv, dAb fragments.
  • detection agents also referred to herein as "binding partners”
  • antibody or antigen-binding fragment thereof such as Fab, F(ab)2, Fv, single chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, scFv, dAb fragments.
  • the antibody or antigen-binding fragment thereof can be monoclonal, chimeric, or humanized.
  • Detection agents also include other peptide molecules and aptamers that bind specifically to a biomarker. Methods for producing antibodies, peptide molecules, and aptamers are well known in
  • the invention provides serotonin and uses thereof evaluating diseases caused by Dengue Virus, e.g., Dengue Fever, Dengue Hemorrhagic Fever and Dengue Shock Syndrome.
  • Serotonin is derived from tryptophan and primarily found in the gastrointestinal tract (GI tract), blood platelets and the central nervous system. Approximately 90% of the serotonin in human body is located in the enterochromaffin cells in the GI tract, and secreted serotonin from the enterochromaffin cells will eventually get into the blood.
  • Blood platelets actively take up serotonin and store it. For platelet to function or to form a plug, three steps are involved: platelet adhesion, inducers release and platelet aggregation.
  • Serotonin is released when the platelets bind to a clot, and serves as a vasoconstrictor to help regulate homeostasis and blood clotting. Serotonin is also a platelet agonist, and has effects on all three steps mentioned above. Low level of serotonin can reduce platelet adhesion by decreasing the secretion of adhesive proteins, and reduce platelet responses to inducers like ADP and thromboxane A2. Thus, decrease of serotonin can adversely affect platelet function and may contribute to the symptoms of DHF like plasma leakage.
  • decreased level of serotonin at the early febrile phase compared to control expression levels indicate a subject at risk of developing or having developed DHF.
  • Cytokines Interferon-gamma (IFN- ⁇ ), Basic Fibroblast Growth Factor (FGF basic), Granulocyte-Colony Stimulating Factor (G-CSF), Interleukin-8 (IL-8), IL10, BDNF, VEGF-A, VEGF-D, IFN-alpha, TNF alpha, bNGF, HGF and PDGF-BB
  • the invention provides cytokines, e.g., interferon-gamma, and uses thereof evaluating diseases caused by Dengue Virus, e.g., Dengue Fever, Dengue Hemorrhagic Fever, and Dengue Shock Syndrome.
  • cytokines refer to cell-signaling molecules, such as proteins, peptides or glycoproteins.
  • cytokines refer to subclasses of cell-signaling molecules, such as interleukins, lymphokines, chemokines and interferons.
  • increased level of interferon-gamma at the early febrile phase e.g., less than about 96 hours after onset of fever
  • control expression levels indicate a subject at risk of developing or having developed DHF.
  • methods provided herein comprise measuring the levels of serotonin and cytokine, e.g., interferon-gamma, in a biological sample and then comparing that level to one or more control levels.
  • the comparing identifies a subject at risk of developing or having developed DHF.
  • a control level is a level of the same biomarker in a biological sample from a control subject or subjects.
  • a control subject may be a normal, healthy subject that shows no Dengue virus-associated symptoms. Dengue virus- associated symptoms include fever, headache, muscle and joint pain, nausea, rashes, vascular leakage, thrombocytopenia, hemorrhage, hypotension and cardiovascular collapse.
  • a control subject may be a subject that presents with one or more Dengue virus-associated symptoms.
  • the control subject may be a subject diagnosed with or suspected of having Dengue Fever.
  • the control subject may be a subject with Dengue Fever that does not develop or is not at risk for developing Dengue Hemorrhagic Fever.
  • a control level is a predetermined level from a control subject or subjects, such that the control level need not be measured every time the methods described herein are performed.
  • Biological samples refer to samples taken or derived from a subject (e.g., a subject who has developed or is at risk of developing dengue hemorrhagic fever).
  • biological samples include tissue samples or fluid samples.
  • biological fluid samples are blood, plasma, serum, urine, saliva, tears, and other bodily fluids.
  • the methods described herein comprise obtaining or providing a biological sample.
  • the biological sample is blood or serum.
  • the biological sample is blood.
  • the biological sample is serum.
  • the biological sample is collected at one time point.
  • the biological sample is collected at less than about 96 hours after fever onset in the subject (>38.0°).
  • the biological sample is collected at more than one time point (e.g., at less than about 96 hours after fever onset, at about 5-7 days after fever onset, and at about >7 days after fever onset).
  • a subject is preferably a human.
  • a subject may be an adult or a child.
  • a subject may be a patient.
  • a subject may present with one or more Dengue virus-associated symptoms.
  • Dengue virus-associated symptoms include, but are not limited to, headache, muscle and joint pain, nausea and rashes.
  • a subject may already be known or suspected of having a Dengue virus infection. Determining if a subject has Dengue virus infection can be accomplished by methods well-known in the art, e.g., viral titer or serology (see, e.g., Dengue hemorrhagic fever:
  • a subject has or is suspected of having a Dengue virus infection. In some embodiments, a subject is suspected of having a Dengue virus infection. In some embodiments, a subject has a Dengue virus infection.
  • a subject has or is suspected of having a primary Dengue virus infection.
  • a subject has or is suspected of having a secondary Dengue virus infection (e.g., a subject who has been previously infected with one Dengue virus serotype and now has or is suspected of having another infection with a different Dengue virus serotype).
  • a subject has or is suspected of having a primary or secondary infection.
  • Primary and secondary Dengue infections can be distinguished from each other using assays known in the art, e.g., a haemagglutination inhibition (HI) assay, an IgM antibody capture ELISA, or an IgG avidity assay (see, e.g., De Souza VA, Fernandes S, Araujo ES, Tateno AF, Olivera OM. Use of an immunoglobulin G avidity test to discriminate between primary and secondary dengue virus infections. J Clin Microbiol . 2004 Apr ; 42: 1782-1784; Matheus S, Deparis X, Labeau B, Lelarge J, Movran J, Dussart P.
  • assays known in the art e.g., a haemagglutination inhibition (HI) assay, an IgM antibody capture ELISA, or an IgG avidity assay (see, e.g., De Souza VA, Fernandes S, Araujo ES, Tateno AF, Olivera
  • a subject has or is at risk of developing DHF. In some embodiments, a subject is at risk of developing DHF. In some embodiments, a subject has or is suspected of having DHF. Symptoms of DHF include, but are not limited to onset of vascular leakage, thrombocytopenia, and hemorrhage.
  • the methods described herein comprise determining whether a statistically significant difference exists between the levels of serotonin and interferon-gamma as described herein and one or more control levels.
  • the statistically significant difference indicates that a subject is at risk of developing or has developed DHF.
  • determining a statistically significant difference comprises performing a statistical test.
  • the statistical test can be one known in the art or described herein, e.g., student's T-test, Chi-squared test, analysis of variance (ANOVA) test, Willcoxon rank sum test, Kruskal- Wallis test, or Pearson product-moment correlation coefficient test. It is to be appreciated that the statistical test can be calculated using a processor, computer, or other calculating device.
  • the methods described herein comprise generating a statistical report or statistically significant profile.
  • the method comprises determining whether a statistically significant difference exists between the levels of serotonin and interferon-gamma and control levels, wherein the presence of a statistically significant difference is indicative of a subject at risk of developing or having developed DHF.
  • the method comprises: a) determining levels of serotonin and interferon-gamma and b) determining whether a statistically significant difference exists between the levels of serotonin and interferon-gamma and control levels, wherein the presence of statistically significant difference is indicative of a subject at risk of developing or having developed DHF.
  • the one or more biomarkers further comprise white blood cell count (WBC), red blood cell count (RBC), blood hemoglobin (HGB), hematocrit (HCT), macrophage cell volume (MCV), mean corpuscular haemoglobin (MCH), Mean corpuscular hemoglobin concentration (MCHC), platelet count (PLT), lymphocyte percentage (LYMPH%), lymphocyte count (LYMPH), mixed cell distribution (MXD), neutrophil percentage ( EUT%), neutrophil count (NEUT), red blood cell distribution width-coefficient of variation (RDW-CV), and viral titers.
  • WBC white blood cell count
  • RBC red blood cell count
  • HGB blood hemoglobin
  • HCT hematocrit
  • MCV macrophage cell volume
  • MCV mean corpuscular haemoglobin
  • MHC mean corpuscular hemoglobin concentration
  • PHT platelet count
  • LYMPH lymphocyte percentage
  • MXD mixed cell distribution
  • EUT neutrophil percentage
  • NEUT red blood cell
  • the method further comprises performing a statistical test. In some embodiments, the method further comprises obtaining a biological sample. In some embodiments, the method further comprises identifying a subject at risk of developing or having developed DHF. In some embodiments, the method further comprises managing treatment of a subject based on the statistically significant difference. In some embodiments, the managing treatment of a subject comprises hospitalization of the subject based on the statistically significant difference.
  • kits and devices for evaluating e.g., identifying, assisting in identifying, diagnosing, assisting in diagnosing, triaging, detecting or assisting in triaging
  • a subject as described herein (e.g., a subject having developed DHF or at risk of developing DHF).
  • the kit or device comprises a first group of binding partners for detecting the biomarkers discussed herein.
  • a binding partner is any molecule that binds specifically to a biomarker.
  • the binding partner is an antibody or antigen-binding fragment thereof, such as Fab, F(ab)2, Fv, single chain antibodies, Fab and sFab fragments, F(ab')2, Fd fragments, scFv, or dAb fragments.
  • Binding partners also include other peptide molecules and aptamers that bind specifically to a biomarker. Methods for producing peptide molecules and aptamers are well known in the art (see, e.g., published US Patent Application No. 2009/0075834, US Patent Nos. 7435542, 30 7807351 and 7239742).
  • the binding partner(s) are bound to a surface.
  • the binding partners may be bound to the surface covalently or non-covalently.
  • the binding partners may be bound directly to the surface, or may be bound indirectly, e.g., through a linker.
  • linkers include, but are not limited to, carbon-containing chains, polyethylene glycol (PEG), nucleic acids, monosaccharide units, and peptides.
  • the surface can be made of any material, e.g., metal, plastic, paper, or any other polymer, or any combination thereof.
  • the device is a dipstick.
  • the surface comprises microfluidic channels.
  • the kit or device comprises binding partners for serotonin and interferon-gamma.
  • the kit or device comprises one or more control binding agents.
  • suitable control binding agents include, but are not limited to, a serum albumin binding partner.
  • the kit or device comprises a second group of binding partners.
  • the second group of binding partners is washed over the biomarkers bound to the first group of binding partners.
  • the second group of binding partners comprises a detectable label (e.g., a flurophor, a biotin, or an enzyme).
  • the second group of binding partners are antibodies or antigen binding fragments thereof.
  • the kit or device comprises a secondary antibody or antibodies comprising a detectable label, wherein the secondary antibody or antibodies that binds to the second group of binding partners.
  • the kit or device generates an output that indicates that a subject has or is at risk for developing DHF.
  • outputs include, but are not limited to, appearance of one or more indicators, a change in one or more indicators, or disappearance of one or more indicators.
  • Suitable indicators include, but are not limited to, a detectable chemical, e.g., fluorescent dyes or colorimetric dyes. The indicators may be measured, e.g., by eye or using a machine such as a spectrometer, a spectroradiometer, or a spectrocolorimeter.
  • kits or devices may be positive, e.g., indicating an increased or elevated level of a biomarker compared to a control, or negative, e.g., indicating a decreased or low level of a biomarker compared to a control.
  • the kit or device contains at least one positive indicator.
  • the kit or device contains at least negative indicator.
  • the kit or device contains at least one positive indicator and at least one negative indicator.
  • the device could be a dipstick that can detect serotonin and interferon- gamma.
  • serotonin is expected to be negative or low in subjects that have or are at risk of developing DHF compared to a subject that has DF.
  • interferon- gamma is expected to be high or positive in subjects that have or are at risk of developing DHF compared to a subject that has DF.
  • serotonin would serve as a negative indicator
  • interferon-gamma would serve as a positive indicator of a subject having or being at risk of developing DHF.

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Abstract

La présente invention concerne un procédé permettant de déterminer qu'un sujet a développé ou présente un risque de développer la dengue hémorragique, le procédé consistant à déterminer une concentration de sérotonine et une concentration de cytokine, par exemple une concentration d'interféron-gamma, dans un échantillon biologique obtenu sur un sujet, et à comparer la concentration de sérotonine et la concentration de cytokine, par exemple d'interféron-gamma, dans l'échantillon biologique à une concentration témoin de sérotonine et une concentration témoin de cytokine, par exemple d'interféron-gamma, où une différence des concentrations de sérotonine et de cytokine, par exemple d'interféron-gamma, dans l'échantillon biologique tel que comparé aux concentrations de la sérotonine témoin et de la cytokine témoin, par exemple d'interféron-gamma, indique que le sujet a développé ou présente un risque de développer une dengue hémorragique.
PCT/US2016/056999 2015-10-14 2016-10-14 Combinaison de sérotonine et d'une cytokine comme prédicteur pronostique précoce de la dengue grave WO2017066538A1 (fr)

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CN111542744A (zh) * 2020-03-10 2020-08-14 深圳迈瑞生物医疗电子股份有限公司 血液分析仪、血液分析方法和计算机可读存储介质
CN111542744B (zh) * 2020-03-10 2024-03-15 深圳迈瑞生物医疗电子股份有限公司 血液分析仪、血液分析方法和计算机可读存储介质

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